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Background: The decline of physical function during chemotherapy predicts poor quality of life and premature death. It is unknown if resistance training prevents physical function decline during chemotherapy in colon cancer survivors., Methods: This multicenter trial randomly assigned 181 colon cancer survivors receiving postoperative chemotherapy to home-based resistance training or usual care control. Physical function outcomes included the short physical performance battery, isometric handgrip strength, and the physical function subscale of the Medical Outcomes Short-Form 36-item questionnaire. Mixed models for repeated measures quantified estimated treatment differences., Results: At baseline, participants had a mean (SD) age of 55.2 (12.8) years; 67 (37%) were 60 years or older, and 29 (16%) had a composite short physical performance battery score of no more than 9. Compared with usual care control, resistance training did not improve the composite short physical performance battery score (estimated treatment difference = -0.01, 95% confidence interval [CI] = -0.32 to 0.31; P = .98) or the short physical performance battery scores for balance (estimated treatment difference = 0.01, 95% CI = -0.10 to 0.11; P = .93), gait speed (estimated treatment difference = 0.08, 95% CI = -0.06 to 0.22; P = .28), and sit-to-stand (estimated treatment difference = -0.08, 95% CI = -0.29 to 0.13; P = .46). Compared with usual care control, resistance training did not improve isometric handgrip strength (estimated treatment difference = 1.50 kg, 95% CI = -1.06 to 4.05; P = .25) or self-reported physical function (estimated treatment difference = -3.55, 95% CI = -10.03 to 2.94); P = .28). The baseline short physical performance battery balance score (r = 0.21, 95% CI = 0.07 to 0.35) and handgrip strength (r = 0.23, 95% CI = 0.09 to 0.36) correlated with chemotherapy relative dose intensity., Conclusion: Among colon cancer survivors with relatively high physical functioning, random assignment to home-based resistance training did not prevent physical function decline during chemotherapy., Clinical Trial Registration: NCT03291951., (© The Author(s) 2024. Published by Oxford University Press.)

Importance: Prior studies demonstrated consistent associations of low skeletal muscle mass assessed on surgical planning scans with postoperative morbidity and mortality. The increasing availability of imaging artificial intelligence enables development of more comprehensive imaging biomarkers to objectively phenotype frailty in surgical patients., Objective: To evaluate the associations of body composition scores derived from multiple skeletal muscle and adipose tissue measurements from automated segmentation of computed tomography (CT) with the Hospital Frailty Risk Score (HFRS) and adverse outcomes after abdominal surgery., Design, Setting, and Participants: This retrospective cohort study used CT imaging and electronic health record data from a random sample of adults who underwent abdominal surgery at 20 medical centers within Kaiser Permanente Northern California from January 1, 2010, to December 31, 2020. Data were analyzed from April 1, 2022, to December 1, 2023., Exposure: Body composition derived from automated analysis of multislice abdominal CT scans., Main Outcomes and Measures: The primary outcome of the study was all-cause 30-day postdischarge readmission or postoperative mortality. The secondary outcome was 30-day postoperative morbidity among patients undergoing abdominal surgery who were sampled for reporting to the National Surgical Quality Improvement Program., Results: The study included 48 444 adults; mean [SD] age at surgery was 61 (17) years, and 51% were female. Using principal component analysis, 3 body composition scores were derived: body size, muscle quantity and quality, and distribution of adiposity. Higher muscle quantity and quality scores were inversely correlated (r = -0.42; 95% CI, -0.43 to -0.41) with the HFRS and associated with a reduced risk of 30-day readmission or mortality (quartile 4 vs quartile 1: relative risk, 0.61; 95% CI, 0.56-0.67) and 30-day postoperative morbidity (quartile 4 vs quartile 1: relative risk, 0.59; 95% CI, 0.52-0.67), independent of sex, age, comorbidities, body mass index, procedure characteristics, and the HFRS. In contrast to the muscle score, scores for body size and greater subcutaneous and intermuscular vs visceral adiposity had inconsistent associations with postsurgical outcomes and were attenuated and only associated with 30-day postoperative morbidity after adjustment for the HFRS., Conclusions and Relevance: In this study, higher muscle quantity and quality scores were correlated with frailty and associated with 30-day readmission and postoperative mortality and morbidity, whereas body size and adipose tissue distribution scores were not correlated with patient frailty and had inconsistent associations with surgical outcomes. The findings suggest that assessment of muscle quantity and quality on CT can provide an objective measure of patient frailty that would not otherwise be clinically apparent and that may complement existing risk stratification tools to identify patients at high risk of mortality, morbidity, and readmission.

Background: Many patients with colon cancer cannot fully adhere to postoperative chemotherapy due to dose-limiting toxicities, resulting in lower relative dose intensity (RDI) and potentially compromising overall survival. This study examined whether home-based resistance training (RT) during adjuvant chemotherapy improves RDI and patient-reported toxicities versus usual care (UC) in colon cancer patients., Methods: Multicenter, randomized control trial (RCT) conducted at community and academic practices. Enrollment of patients receiving postoperative chemotherapy for colon cancer occurred between February 23, 2018, and September 29, 2021; final follow-up was March 21, 2022. Participants were randomized to RT (n = 90) or UC (n = 91) for the duration of chemotherapy. Participants in the RT group engaged in twice weekly home-based progressive RT. At the end of the study, UC was given an online exercise program., Results: Among 181 randomized patients (mean age, 55.2 [SD, 12.8] years, 95 [52.5%] were men), there were no differences in the mean RDI among those in RT (79% [SD, 19%]) and those in UC (82% [SD, 19%]); (mean difference -0.04 [95% confidence interval (CI), -0.09 to 0.02]). Assignment to RT did not significantly reduce the number of moderate/severe symptoms per week across follow-up (relative rate: 0.94 [95% CI, 0.72-1.22]). Additionally, time since randomization did not significantly modify the effect of RT on the overall number of symptoms (p = .06)., Conclusions: Among patients with colon cancer, these results do not support home-based RT as an adjunct to chemotherapy specifically to improve planned treatment intensity., (© 2024 American Cancer Society.)

Background & Aims: Measurements (amount, distribution, and radiodensity) of muscle and adipose tissue were reported to be individually associated with overall survival in patients with breast cancer. However, they were not typically combined to develop an overall risk score, which can identify patients at high risk of death and prioritize patients in need of dietary and lifestyle interventions. Thus, we aimed to develop a novel composite body composition risk score (B-Score)., Methods: We included 3105 patients with stage II or III breast cancer at Kaiser Permanente Northern California and Dana Farber Cancer Institute. From CT scans at diagnosis, we assessed areas and radiodensity of muscle and adipose tissue at the third lumber vertebrae. We considered skeletal muscle index (SMI), subcutaneous adipose tissue index (SATI) and SAT radiodensity as they were independent prognostic factors for overall survival. Each measurement was dichotomized using optimal stratification, with low SMI (<40.1 cm 2 /m 2 ), high SATI (≥75.7 cm 2 /m 2 ), and high SAT radiodensity (≥-97.2HU) considered risk factors. We calculated B-Score as the sum of these factors and estimated its association with overall survival using Cox proportional hazards regression with adjustment for clinicopathologic factors., Results: Mean (standard deviation) age was 53.9 (11.8) years, 70.3% were Non-Hispanic White, and 60.5% were stage II. Most patients (60.6%) had only one body composition risk factor (B-Score = 1). Compared to those with no risk factors (B-Score = 0), the risk of death increased with more body composition risk factors: the adjusted hazard ratios were 1.10 (95% CI: 0.85, 1.42), 1.47 (95% CI: 1.12, 1.92), and 2.11 (95% CI: 1.26, 3.53) for B-Scores of 1, 2, and 3, respectively (P trend < 0.001)., Conclusions: More unfavorable body composition characteristics were associated with increased risks of overall mortality in a dose-response manner. Considering body composition measurements together as a composite score (B-Score) may improve risk stratification and inform dietary and lifestyle interventions following breast cancer diagnosis., Competing Interests: Conflicts of interest Carla M. Prado reported honoraria and/or paid consultancy from Abbott Nutrition, Nutricia, Nestle Health Science, and Amra Medical, and Pfizer. Others did not claim conflict of interest., (Copyright © 2024 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.)

Background: The impact of alcohol consumption on breast cancer (BC) prognosis remains unclear., Methods: The authors examined short-term alcohol intake in relation to recurrence and mortality in 3659 women who were diagnosed with stage I-IV BC from 2003 to 2013 in the Pathways Study. Alcohol drinking in the past 6 months was assessed at cohort entry (mean, 2 months postdiagnosis) and 6 months later using a food-frequency questionnaire. Study end points were recurrence and death from BC, cardiovascular disease, and all causes. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using multivariable Cox proportional hazards models., Results: Over an average follow-up of 11.2 years, 524 recurrences and 834 deaths (369 BC-specific and 314 cardiovascular disease-specific) occurred. Compared with nondrinkers (36.9%), drinkers were more likely younger, more educated, and current or past smokers. Overall, alcohol consumption was not associated with recurrence or mortality. However, women with higher body mass index (BMI ≥ 30 kg/m 2 ) had lower risk of overall mortality with increasing alcohol consumption for occasional drinking (HR, 0.71; 95% CI, 0.54-0.94) and regular drinking (HR, 0.77; 95% CI, 0.56-1.08) around the time of diagnosis, along with 6 months later, in a dose-response manner (p < .05). Women with lower BMI (<30 kg/m 2 ) were not at higher risk of mortality but were at possibly higher, yet nonsignificant, risk of recurrence for occasional drinking (HR, 1.29; 95% CI, 0.97-1.71) and regular drinking (HR, 1.19; 95% CI, 0.88-1.62)., Conclusions: Alcohol drinking around the time of and up to 6 months after BC diagnosis was associated with lower risk of all-cause mortality in obese women. A possible higher risk of recurrence was observed in nonobese women., (© 2023 American Cancer Society.)

Background: The number of breast cancer survivors is increasing, yet evidence to inform dietary and lifestyle guidelines is limited., Methods: This analysis included 3,658 participants from the Pathways Study, a prospective cohort of women diagnosed with invasive breast cancer. A healthy plant-based dietary index score (hPDI), an American Cancer Society (ACS) nutrition guidelines score, a 2015 Healthy Eating Index score (HEI), hours per week of moderate to vigorous physical activity (PA), and lifetime cumulative pack-years of cigarette smoking (SM) were each measured at diagnosis, 6, 24, and 72 months. Using g-computation, 5- and 10-year risk ratios (RR), risk differences, and 95% confidence intervals (CI) for all-cause mortality under hypothetical interventions on diet quality, PA, and SM, compared with the natural course (no intervention) were calculated., Results: Hypothetical moderate to extreme interventions on hPDI, ACS, and HEI, each in combination with PA and SM, showed 11% to 56%, 9% to 38%, and 9% to 49% decreases in 5-year risks of all-cause mortality compared with no intervention, respectively [(hPDI: RRmoderate = 0.89, 95% CI: 0.82-0.94; RRextreme = 0.44, 95% CI: 0.26-0.67), (ACS: RRmoderate = 0.91, 95% CI: 0.85-0.96; RRextreme = 0.62, 95% CI: 0.43-0.82), (HEI: RRmoderate = 0.91, 95% CI: 0.84-0.95; RRextreme = 0.51, 95% CI: 0.33-0.72)]. While 10-year relative risks were slightly attenuated, absolute risk reductions were more pronounced., Conclusions: Interventions to improve diet quality, increase PA, or reduce SM at the time of diagnosis may improve survival among breast cancer survivors., Impact: We estimate that over 10% of deaths could be delayed by even moderate adoption of these behaviors., (©2023 American Association for Cancer Research.)

Background: Low skeletal muscle mass (myopenia) is common in cancer populations and is associated with functional decline and mortality, but prior oncology studies did not assess total body skeletal muscle mass. Instead, they measured surrogates such as cross-sectional area (CSA) of skeletal muscle at L3 from computed tomography (CT) or appendicular lean mass (ALM) from dual-energy X-ray absorptiometry (DXA). D3-creatine (D3Cr) dilution is a non-invasive method to assess total body skeletal muscle mass, which has been examined in a variety of populations but not in cancer. To compare the associations of D3Cr muscle mass, CT CSA, and DXA ALM with myopenia and physical function, we conducted a cross-sectional study among 119 patients with colon cancer (2018-2022)., Methods: For each technique (D3Cr, CT and DXA), myopenia was defined as the lowest sex-specific quartile of its measurement. Physical function was measured by the short physical performance battery and grip strength. We calculated Pearson correlations (r) among three techniques, computed Cohen's kappa coefficients (κ) to assess the agreement of myopenia, and estimated Pearson correlations (r) of three techniques with physical function. All analyses were sex-specific., Results: Sixty-one (51.3%) participants were male, the mean (standard deviation) age was 56.6 (12.9) years, and most (68.9%) had high physical function (short physical performance battery: ≥11 points). Correlations and myopenia agreement among three techniques were greater in men than women; for example, regarding D3Cr muscle mass versus CT CSA, r was 0.73 (P < 0.001) for men versus 0.45 (P < 0.001) for women, and κ was 0.82 (95% CI: 0.65, 0.99) for men versus 0.24 (95% CI: -0.08, 0.52) for women. Among men, higher D3Cr muscle mass was significantly correlated with faster gait speed (r = 0.43, P < 0.01) and stronger grip strength (r = 0.32, P < 0.05); similar correlations were observed for CT CSA and DXA ALM. However, among women, no measure of muscle or lean mass was significantly associated with physical function., Conclusions: This is the first study using D3-creatine dilution method to assess muscle mass in a cancer population. Regardless of the techniques used for muscle or lean mass assessment, we observed stronger correlations, greater myopenia agreement, and more significant associations with physical function in men with colon cancer than women. D3Cr, CT and DXA are not interchangeable methods for assessing myopenia and physical function, especially in women with colon cancer. Future studies should consider relative advantages of these techniques and examine the D3-creatine dilution method in other cancer types., (© 2023 The Authors. Journal of Cachexia, Sarcopenia and Muscle published by Wiley Periodicals LLC.)

Background: Despite evidence that low muscle increases the risk of chemotoxicity, most chemotherapies are dosed on body surface area without considering body composition. Among 178 patients with colon cancer, we assessed muscle and adipose tissue with multiple techniques and examined their associations with relative dose intensity (RDI) and adverse events., Methods: We estimated (i) cross-sectional skeletal muscle area (SMA) and total adipose tissue (TAT) area at L3 from computed tomography (CT); (ii) appendicular lean mass (ALM) and total body fat (TBF) mass from dual-energy X-ray absorptiometry (DXA); and (iii) total body skeletal muscle mass using D3-creatine (D3Cr) dilution. We standardized each measurement by its sex-specific standard deviation (SD). The primary outcome was reduced RDI (RDI <85%). The secondary outcome was the number of moderate and severe adverse events during each cycle of chemotherapy. We estimated the associations of muscle and adipose tissue measurements (per SD increase) with reduced RDI using logistic regression and adverse events using generalized estimating equations for repeated measures., Results: Higher CT SMA and DXA ALM were significantly associated with a lower risk of reduced RDI [odds ratios: 0.56 (0.38-0.81) for CT SMA; 0.56 (0.37-0.84) for DXA ALM]. No measurements of muscle or adipose tissue were associated with adverse events., Conclusions: More muscle was associated with improved chemotherapy completion among patients with colon cancer, whereas muscle and adipose tissue were not associated with adverse events., Impact: Considering body composition may help personalize dosing for colon cancer chemotherapy by identifying patients at risk for poor chemotherapy outcomes., (©2023 American Association for Cancer Research.)

Objective: To evaluate changes in physical function (PF) for older women with endometrial cancer (EC) + / - adjuvant therapy in the Women's Health Initiative Life and Longevity after Cancer cohort., Materials and Methods: This study examined women ≥ 70 years of age with EC with available treatment records. Change in PF was measured using the RAND-36 and compared between groups using Wilcoxon rank-sum tests. Multivariable median regression was used to compare the changes in scores while adjusting for confounding variables., Results: Included in the study were 287 women, 150 (52.3%) women who did not receive adjuvant therapy and 137 (47.7%) who received adjuvant therapy. When comparing PF scores, there was a statistically significant difference in the median percent change in functional decline, with a greater decline in those who received adjuvant therapy (- 5.9% [- 23.5 to 0%]) compared to those who did not (0 [- 18.8 to + 6.7%]), p = 0.02). Results were not statistically significant after multivariable adjustment, but women who underwent chemotherapy had a greater percent change (median ∆ - 13.8% [- 35.5 to 0%]) compared to those who received radiation alone (median ∆ - 5.9% [- 31.3 to 0%]) or chemotherapy and radiation (median ∆ - 6.5% [- 25.8 to + 5.7%]., Conclusions: Older women with EC who received adjuvant therapy experienced greater change in PF than those who did not receive adjuvant therapy, particularly women who received chemotherapy. These results were not statistically significant on multivariate analysis., Implications for Cancer Survivors: EC survivors may experience changes in PF because of chemotherapy and/or radiation therapy. Additional supportive care may need to be provided to older women to mitigate functional decline., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Lifestyle habits can impact breast cancer development, but its impact on breast cancer prognosis remains unclear. We investigated associations of post-diagnosis lifestyle with mortality and recurrence in 1,964 women with invasive breast cancer enrolled in the Kaiser Permanente Northern California Pathways Study shortly after diagnosis with lifestyle information at baseline (2005-2013) and the 2-year follow-up., Methods: We calculated a post-diagnosis lifestyle score (range, 0-18) based on 9 diet, physical activity, and body weight recommendations from the American Cancer Society/American Society of Clinical Oncology (ACS/ASCO) using follow-up data (body weight also included baseline data); higher scores indicate greater guideline concordance. Similarly, we calculated a pre-diagnosis lifestyle score using baseline data to investigate pre- to post-diagnosis changes. We estimated hazard ratios (HR) and 95% confidence intervals (CI) using Cox proportional hazard models, with follow-up through December 2018 (observing 290 deaths and 176 recurrences)., Results: The 2-year post-diagnosis lifestyle score was inversely associated with all-cause mortality (ACM; HR per 2-point increase = 0.90; 95% CI, 0.82-0.98), and breast cancer-related mortality (HR, 0.79; 95% CI, 0.67-0.95), but not recurrence. Relative to women who maintained low concordance with recommendations at both time points, women who maintained high concordance had a lower risk of ACM (HR, 0.61, 95% CI, 0.37-1.03). Improved concordance with some specific recommendations (particularly PA) may be associated with a lower hazard of ACM (HRPA, 0.52; 95% CI, 0.35-0.78)., Conclusions: Results suggest that women with breast cancer may benefit from a post-diagnosis lifestyle aligned with ACS/ASCO guidelines., Impact: This information may potentially guide lifestyle recommendations for breast cancer survivors to reduce mortality risk., (©2023 American Association for Cancer Research.)

Intermittent fasting entails restricting food intake during specific times of day, days of the week, religious practice, or surrounding clinically important events. Herein, the metabolic and circadian rhythm mechanisms underlying the proposed benefits of intermittent fasting for the cancer population are described. We summarize epidemiological, preclinical, and clinical studies in cancer published between January 2020 and August 2022 and propose avenues for future research. An outstanding concern regarding the use of intermittent fasting among cancer patients is that fasting often results in caloric restriction, which can put patients already prone to malnutrition, cachexia, or sarcopenia at risk. Although clinical trials do not yet provide sufficient data to support the general use of intermittent fasting in clinical practice, this summary may be useful for patients, caregivers, and clinicians who are exploring intermittent fasting as part of their cancer journey for clinical outcomes and symptom management., (© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Cachexia, a systemic wasting condition, is considered a late consequence of diseases, including cancer, organ failure, or infections, and contributes to significant morbidity and mortality. The induction process and mechanistic progression of cachexia are incompletely understood. Refocusing academic efforts away from advanced cachexia to the etiology of cachexia may enable discoveries of new therapeutic approaches. Here, we review drivers, mechanisms, organismal predispositions, evidence for multi-organ interaction, model systems, clinical research, trials, and care provision from early onset to late cachexia. Evidence is emerging that distinct inflammatory, metabolic, and neuro-modulatory drivers can initiate processes that ultimately converge on advanced cachexia., Competing Interests: Declaration of interests S.O. receives remuneration for scientific advisory services provided to Pfizer, AstraZeneca, Courage Therapeutics, and Third Rock Ventures. M.J.-H. has consulted for, and is a member of, the Achilles Therapeutics Scientific Advisory Board and Steering Committee, has received speaker honoraria from Pfizer, Astex Pharmaceuticals, Oslo Cancer Cluster, and is co-inventor on a European patent application relating to methods to detect lung cancer (PCT/US2017/028013). All authors, other than J.G. and D.M., are members of the CANCAN Grand Challenge Team funded by Cancer Research UK and the National Cancer Institute. The funders had no role in writing or reviewing the manuscript., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Importance: Patients with cancer experience acute declines in physical function, hypothesized to reflect accelerated aging driven by cancer-related symptoms and effects of cancer therapies. No study has examined long-term trajectories of physical function by cancer site, stage, or treatment compared with cancer-free controls., Objective: Examine trajectories of physical function a decade before and after cancer diagnosis among older survivors and cancer-free controls., Design, Setting, and Participants: This prospective cohort study enrolled patients from 1993 to 1998 and followed up until December 2020. The Women's Health Initiative, a diverse cohort of postmenopausal women, included 9203 incident cancers (5989 breast, 1352 colorectal, 960 endometrial, and 902 lung) matched to up to 5 controls (n = 45 358) on age/year of enrollment and study arm., Exposures: Cancer diagnosis (site, stage, and treatment) via Medicare and medical records., Main Outcomes and Measures: Trajectories of self-reported physical function (RAND Short Form 36 [RAND-36] scale; range: 0-100, higher scores indicate superior physical function) estimated from linear mixed effects models with slope changes at diagnosis and 1-year after diagnosis., Results: This study included 9203 women with cancer and 45 358 matched controls. For the women with cancer, the mean (SD) age at diagnosis was 73.0 (7.6) years. Prediagnosis, physical function declines of survivors with local cancers were similar to controls; after diagnosis, survivors experienced accelerated declines relative to controls, whose scores declined 1 to 2 points per year. Short-term declines in the year following diagnosis were most severe in women with regional disease (eg, -5.3 [95% CI, -6.4 to -4.3] points per year in regional vs -2.8 [95% CI, -3.4 to -2.3] for local breast cancer) or who received systemic therapy (eg, for local endometrial cancer, -7.9 [95% CI, -12.2 to -3.6] points per year with any chemotherapy; -3.1 [95% CI, -6.0 to -0.3] with radiation therapy alone; and -2.6 [95% CI, -4.2 to -1.0] with neither, respectively). While rates of physical function decline slowed in the later postdiagnosis period (eg, women with regional colorectal cancer declined -4.3 [95% CI, -5.9 to -2.6] points per year in the year following diagnosis vs -1.4 [95% CI, -1.7 to -1.0] points per year in the decade thereafter), survivors had estimated physical function significantly below that of age-matched controls 5 years after diagnosis., Conclusions and Relevance: In this prospective cohort study, survivors of cancer experienced accelerated declines in physical function after diagnosis, and physical function remained below that of age-matched controls even years later. Patients with cancer may benefit from supportive interventions to preserve physical functioning.

Importance: The association of chronic inflammation with colorectal cancer recurrence and death is not well understood, and data from large well-designed prospective cohorts are limited., Objective: To assess the associations of inflammatory biomarkers with survival among patients with stage III colon cancer., Design, Setting, and Participants: This cohort study was derived from a National Cancer Institute-sponsored adjuvant chemotherapy trial Cancer and Leukemia Group B/Southwest Oncology Group 80702 (CALGB/SWOG 80702) conducted between June 22, 2010, and November 20, 2015, with follow-up ending on August 10, 2020. A total of 1494 patients with plasma samples available for inflammatory biomarker assays were included. Data were analyzed from July 29, 2021, to February 27, 2022., Exposures: Plasma inflammatory biomarkers (interleukin 6 [IL-6], soluble tumor necrosis factor α receptor 2 [sTNF-αR2], and high-sensitivity C-reactive protein [hsCRP]; quintiles) that were assayed 3 to 8 weeks after surgery but before chemotherapy randomization., Main Outcomes and Measures: The primary outcome was disease-free survival, defined as time from randomization to colon cancer recurrence or death from any cause. Secondary outcomes were recurrence-free survival and overall survival. Hazard ratios for the associations of inflammatory biomarkers and survival were estimated via Cox proportional hazards regression., Results: Of 1494 patients (median follow-up, 5.9 years [IQR, 4.7-6.1 years]), the median age was 61.3 years (IQR, 54.0-68.8 years), 828 (55.4%) were male, and 327 recurrences, 244 deaths, and 387 events for disease-free survival were observed. Plasma samples were collected at a median of 6.9 weeks (IQR, 5.6-8.1 weeks) after surgery. The median plasma concentration was 3.8 pg/mL (IQR, 2.3-6.2 pg/mL) for IL-6, 2.9 × 103 pg/mL (IQR, 2.3-3.6 × 103 pg/mL) for sTNF-αR2, and 2.6 mg/L (IQR, 1.2-5.6 mg/L) for hsCRP. Compared with patients in the lowest quintile of inflammation, patients in the highest quintile of inflammation had a significantly increased risk of recurrence or death (adjusted hazard ratios for IL-6: 1.52 [95% CI, 1.07-2.14]; P = .01 for trend; for sTNF-αR2: 1.77 [95% CI, 1.23-2.55]; P < .001 for trend; and for hsCRP: 1.65 [95% CI, 1.17-2.34]; P = .006 for trend). Additionally, a significant interaction was not observed between inflammatory biomarkers and celecoxib intervention for disease-free survival. Similar results were observed for recurrence-free survival and overall survival., Conclusions and Relevance: This cohort study found that higher inflammation after diagnosis was significantly associated with worse survival outcomes among patients with stage III colon cancer. This finding warrants further investigation to evaluate whether anti-inflammatory interventions may improve colon cancer outcomes., Trial Registration: ClinicalTrials.gov Identifier: NCT01150045.

Short and long sleep duration are associated with adverse metabolic outcomes, such as obesity and diabetes. We evaluated cross-sectional differences in metabolite levels between women with self-reported habitual short (<7 h), medium (7-8 h), and long (≥9 h) sleep duration to delineate potential underlying biological mechanisms. In total, 210 metabolites were measured via liquid chromatography-mass spectrometry in 9207 women from the Nurses' Health Study (NHS; N = 5027), the NHSII (N = 2368), and the Women's Health Initiative (WHI; N = 2287). Twenty metabolites were consistently (i.e. praw < .05 in ≥2 cohorts) and/or strongly (pFDR < .05 in at least one cohort) associated with short sleep duration after multi-variable adjustment. Specifically, levels of two lysophosphatidylethanolamines, four lysophosphatidylcholines, hydroxyproline and phenylacetylglutamine were higher compared to medium sleep duration, while levels of one diacylglycerol and eleven triacylglycerols (TAGs; all with ≥3 double bonds) were lower. Moreover, enrichment analysis assessing associations of metabolites with short sleep based on biological categories demonstrated significantly increased acylcarnitine levels for short sleep. A metabolite score for short sleep duration based on 12 LASSO-regression selected metabolites was not significantly associated with prevalent and incident obesity and diabetes. Associations of single metabolites with long sleep duration were less robust. However, enrichment analysis demonstrated significant enrichment scores for four lipid classes, all of which (most markedly TAGs) were of opposite sign than the scores for short sleep. Habitual short sleep exhibits a signature on the human plasma metabolome which is different from medium and long sleep. However, we could not detect a direct link of this signature with obesity and diabetes risk., (© The Author(s) 2022. Published by Oxford University Press on behalf of Sleep Research Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Research on the impact of metabolic abnormalities on breast cancer prognosis is limited by small samples and assessment of laboratory values at a single time point, often prior to cancer diagnosis and treatment. In this population-based cohort, time-updated laboratory values were adjusted for cancer treatment to assess the association between metabolic risk factors (glucose, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), triglycerides) and breast cancer survival., Methods: 13,434 women diagnosed with stage I-III breast cancer from 2005-15 at Kaiser Permanente were included. All outpatient fasting glucose, HDL-C, LDL-C, and triglyceride values from diagnosis through 2019 or death were extracted from electronic medical records. Risk of breast cancer-specific mortality was evaluated with Cox proportional hazards models adjusted for metabolic labs, demographics, body mass index, diabetes, dyslipidemia and anti-hypertensive medications, tumor characteristics (stage, ER and HER2 receptor status) and cancer treatment (use of chemotherapy, tamoxifen, and aromatase inhibitors)., Results: Mean (SD) age at diagnosis was 62.3 (11.8) years. Over a median follow-up of 8.6 years, 2,876 patients died; 1,080 of breast cancer. Patients with low HDL-C (≤ 45 vs. > 45 mg/dL) had higher breast cancer-specific mortality (HR, 1.77; 95% CI, 1.53-2.05), as did those with elevated fasting glucose (> 99 vs. 60-99 mg/dL) (HR, 1.19; 95% CI, 1.03-1.37). Elevated levels of triglycerides and LDL-C were not associated with breast cancer-specific mortality., Conclusions: High fasting glucose and low HDL-C evaluated over time after cancer diagnosis were associated with higher breast cancer mortality independent of cancer treatments and changes in other metabolic risk factors. Future studies should address whether pharmacologic or lifestyle treatment of glucose and lipids after breast cancer diagnosis can optimize survival outcomes., (© 2022. The Author(s).)

Background: Computed tomography (CT) scans are routinely obtained in oncology and provide measures of muscle and adipose tissue predictive of morbidity and mortality. Automated segmentation of CT has advanced past single slices to multi-slice measurements, but the concordance of these approaches and their associations with mortality after cancer diagnosis have not been compared., Methods: A total of 2871 patients with colorectal cancer diagnosed during 2012-2017 at Kaiser Permanente Northern California underwent abdominal CT scans as part of routine clinical care from which mid-L3 cross-sectional areas and multi-slice T12-L5 volumes of skeletal muscle (SKM), subcutaneous adipose (SAT), visceral adipose (VAT) and intermuscular adipose (IMAT) tissues were assessed using Data Analysis Facilitation Suite, an automated multi-slice segmentation platform. To facilitate comparison between single-slice and multi-slice measurements, sex-specific z-scores were calculated. Pearson correlation coefficients and Bland-Altman analysis were used to quantify agreement. Cox models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for death adjusting for age, sex, race/ethnicity, height, and tumour site and stage., Results: Single-slice area and multi-slice abdominal volumes were highly correlated for all tissues (SKM R = 0.92, P < 0.001; SAT R = 0.97, P < 0.001; VAT R = 0.98, P < 0.001; IMAT R = 0.89, P < 0.001). Bland-Altman plots had a bias of 0 (SE: 0.00), indicating high average agreement between measures. The limits of agreement were narrowest for VAT ( ±  0.42 SD) and SAT ( ±  0.44 SD), and widest for SKM ( ±  0.78 SD) and IMAT ( ±  0.92 SD). The HRs had overlapping CIs, and similar magnitudes and direction of effects; for example, a 1-SD increase in SKM area was associated with an 18% decreased risk of death (HR = 0.82; 95% CI: 0.72-0.92), versus 15% for volume from T12 to L5 (HR = 0.85; 95% CI: 0.75-0.96)., Conclusions: Single-slice L3 areas and multi-slice T12-L5 abdominal volumes of SKM, VAT, SAT and IMAT are highly correlated. Associations between area and volume measures with all-cause mortality were similar, suggesting that they are equivalent tools for population studies if body composition is assessed at a single timepoint. Future research should examine longitudinal changes in multi-slice tissues to improve individual risk prediction., (© 2022 The Authors. Journal of Cachexia, Sarcopenia and Muscle published by John Wiley & Sons Ltd on behalf of Society on Sarcopenia, Cachexia and Wasting Disorders.)

Background & Aims: Computed tomography (CT) scans can measure quantity and distribution of adipose tissue, which are associated with breast cancer prognosis. As a novel prognostic marker, radiodensity of adipose tissue has been examined in multiple cancer types, but never in breast cancer. Lower density indicates larger adipocytes with greater lipid content, whereas higher density can reflect inflammation, fibrosis, vascularity, or even metabolic changes; and both may impact breast cancer prognosis., Methods: We included 2868 nonmetastatic patients with breast cancer diagnosed between January 2005 and December 2013 at Kaiser Permanente Northern California, an integrated healthcare system. From CT scans at diagnosis, we assessed the radiodensity of subcutaneous (SAT) and visceral adipose tissue (VAT) at the third lumbar vertebra and categorized their radiodensity into three levels: low (<1 standard deviation [SD] below the mean), middle (mean ± 1 SD), and high (>1 SD above the mean). Using multivariable Cox proportional hazards regression with adjustment for clinicopathological characteristics including body mass index, we calculated hazard ratios (HRs [95% confidence intervals]) for the associations of adipose tissue radiodensity with overall mortality and breast-cancer-specific mortality., Results: Median age at diagnosis of breast cancer was 56.0 years, most (63.3%) were non-Hispanic White and nearly half (45.6%) were stage II. Compared to middle SAT radiodensity, high SAT radiodensity was significantly associated with increased risk of overall mortality (HR: 1.45 [1.15-1.81]), non-significantly with breast-cancer-specific mortality (HR: 1.32 [0.95-1.84]). Neither low SAT radiodensity nor high or low VAT radiodensity was significantly associated with overall or breast-cancer-specific mortality., Conclusions: High radiodensity of SAT at diagnosis of nonmetastatic breast cancer was associated with increased risk of overall mortality, independent of adiposity and other prognostic factors. Considering both radiodensity and quantity of adipose tissue at different locations could deepen understanding of the role of adiposity in breast cancer survival., Competing Interests: Conflicts of interest Melinda L. Irwin was supported in part by Breast Cancer Research Foundation. Carla M. Prado reported honoraria from Abbott Nutrition, Nestle Health Science, and Fresenius Kabi; and paid consultancy from Nutricia and Pfizer. Others did not claim conflict of interest., (Copyright © 2022 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.)

Background: Although adherence to the American Cancer Society (ACS) Guidelines on Nutrition and Physical Activity for Cancer Prevention associates with lower risk of obesity-related cancer (ORC) incidence and mortality, evidence in Black and Latina women is limited. This association was examined in Black and Latina participants in the Women's Health Initiative (WHI)., Methods: Semi-Markov multistate model examined the association between ACS guideline adherence and ORC incidence and mortality in the presence of competing events, combined and separately, for 9301 Black and 4221 Latina postmenopausal women. Additionally, ACS guideline adherence was examined in a subset of less common ORCs and potential effect modification by neighborhood socioeconomic status and smoking., Results: Over a median of 11.1, 12.5, and 3.7 years of follow-up for incidence, nonconditional mortality, and conditional mortality, respectively, 1191 ORCs (Black/Latina women: 841/269), 1970 all-cause deaths (Black/Latina women: 1576/394), and 341 ORC-related deaths (Black/Latina women: 259/82) were observed. Higher ACS guideline adherence was associated with lower ORC incidence for both Black (cause-specific hazard ratio [CSHR] highvs.low : 0.72; 95% CI, 0.55-0.94) and Latina (CSHR highvs.low : 0.58, 95% CI, 0.36-0.93) women; but not conditional all-cause mortality (Black hazard ratio [HR] highvs.low : 0.86; 95% CI, 0.53-1.39; Latina HR highvs.low : 0.81; 95% CI, 0.32-2.06). Higher adherence was associated with lower incidence of less common ORC (P trend  = .025), but conditional mortality events were limited. Adherence and ORC-specific deaths were not associated and there was no evidence of effect modification., Conclusions: Adherence to the ACS guidelines was associated with lower risk of ORCs and less common ORCs but was not for conditional ORC-related mortality., Lay Summary: Evidence on the association between the American Cancer Society Guidelines on Nutrition and Physical Activity for Cancer Prevention and cancer remains scarce for women of color. Adherence to the guidelines and risk of developing one of 13 obesity-related cancers among Black and Latina women in the Women's Health Initiative was examined. Women who followed the lifestyle guidelines had 28% to 42% lower risk of obesity-related cancer. These findings support public health interventions to reduce growing racial/ethnic disparities in obesity-related cancers., (© 2022 American Cancer Society.)

Purpose: The increasing availability of clinical imaging tests (especially CT and MRI) that directly quantify adipose tissue has led to a rapid increase in studies examining the relationship of visceral, subcutaneous, and overall adiposity to cancer survival. To summarize this emerging body of literature, we conducted a systematic review and meta-analysis of imaging-measured as well as anthropometric proxies for adipose tissue distribution and cancer survival across a wide range of cancer types., Methods: Using keywords related to adiposity, cancer, and survival, we conducted a systematic search of the literature in PubMed and MEDLINE, Embase, and Web of Science Core Collection databases from database inception to 30 June 2021. We used a random-effect method to calculate pooled hazard ratios (HR) and corresponding 95% confidence intervals (CI) within each cancer type and tested for heterogeneity using Cochran's Q test and the I 2 test., Results: We included 203 records for this review, of which 128 records were utilized for quantitative analysis among 10 cancer types: breast, colorectal, gastroesophageal, head and neck, hepatocellular carcinoma, lung, ovarian, pancreatic, prostate, and renal cancer. We found that imaging-measured visceral, subcutaneous, and total adiposity were not significantly associated with increased risk of overall mortality, death from primary cancer, or cancer progression among patients diagnosed with these 10 cancer types; however, we found significant or high heterogeneity for many cancer types. For example, heterogeneity was similarly high when the pooled HRs (95% CI) for overall mortality associated with visceral adiposity were essentially null as in 1.03 (0.55, 1.92; I 2  = 58%) for breast, 0.99 (0.81, 1.21; I 2  = 71%) for colorectal, versus when they demonstrated a potential increased risk 1.17 (0.85, 1.60; I 2  = 78%) for hepatocellular carcinoma and 1.62 (0.90, 2.95; I 2  = 84%) for renal cancer., Conclusion: Greater adiposity at diagnosis (directly measured by imaging) is not associated with worse survival among cancer survivors. However, heterogeneity and other potential limitations were noted across studies, suggesting differences in study design and adiposity measurement approaches, making interpretation of meta-analyses challenging. Future work to standardize imaging measurements and data analyses will strengthen research on the role of adiposity in cancer survival., (© 2022. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Background & Aims: Patients with colon cancer who prematurely discontinue postoperative chemotherapy may have an increased risk of disease recurrence and death. This study tested the hypothesis that the quantity and distribution of abdominal adipose tissue predict premature chemotherapy discontinuation., Methods: This cohort study included 533 patients with stage II-III colon cancer who initiated a planned regimen of 24-weeks of 5-fluorouracil, leucovorin, and oxaliplatin (FOLFOX) chemotherapy. The primary exposures were body mass index (BMI) and computed tomography-derived abdominal adiposity measures (e.g., visceral, subcutaneous, and intramuscular adipose tissue). The primary endpoint was premature chemotherapy discontinuation, defined as receiving <6 cycles of FOLFOX. Generalized linear models quantified the relative risk (RR) of premature chemotherapy discontinuation adjusted for age, sex, cancer stage, height, and muscle area, using two-sided statistical tests., Results: Forty-two patients [7.9% (95% CI: 5.7, 10.5)] prematurely discontinued chemotherapy. Visceral adipose tissue [RR: 3.27 (95% CI: 1.26, 8.49)] and intramuscular adipose tissue [RR: 2.79 (95% CI: 1.09, 7.12)] were statistically significantly associated with an increased risk of premature chemotherapy discontinuation. BMI [RR: 2.07 (95% CI: 0.75, 5.73)] and subcutaneous adipose tissue [RR: 2.32 (95% CI: 0.91, 5.94)] were not statistically significantly associated with premature chemotherapy discontinuation., Conclusion: Among patients with stage II-III colon cancer who initiate postoperative chemotherapy, excess visceral and intramuscular adiposity may be risk factors for the premature discontinuation of chemotherapy., Competing Interests: Conflict of interest Dr. Brown reports receiving grants from the National Cancer Institute and the American Institute for Cancer Research during the conduct of the study. Dr. Cespedes Feliciano reports receiving grants from the National Cancer Institute during the conduct of the study. Dr. Meyerhardt reports receiving grants from the National Cancer Institute during the conduct of the study and reports receiving consulting fees from Cota Healthcare, and Taiho during the 36 months before publication (all fees <$5000). Dr. Caan reports receiving grants from the National Cancer Institute during the conduct of the study. All other authors report no disclosures., (Copyright © 2022 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.)

Background: The mechanisms underlying the association of overall and central body fatness with poorer breast cancer outcomes remain unclear; altered gene and/or protein expression of the adipokines and their receptors in breast tumors might play a role., Methods: In a sample of Black and White women with primary invasive breast cancer, we investigated associations of body mass index (BMI), waist circumference, hip circumference, waist-to-hip ratio (WHR), fat mass index (FMI), and percent body fat with protein expression (log-transformed, n = 722) and gene expression (log2-transformed, n = 148) of leptin (LEP), leptin receptor (LEPR), adiponectin (ADIPOQ), and adiponectin receptors 1 and 2 (ADIPOR1, ADIPOR2). Multivariable linear models, adjusting for race, menopausal status, and estrogen receptor status, were used to assess these associations, with Bonferroni correction for multiple comparisons., Results: In multivariable models, we found that increasing BMI (β = 0.0529, 95% CI: 0.0151, 0.0906) and FMI (β = 0.0832, 95% CI: 0.0268, 0.1397) were associated with higher LEP gene expression, corresponding to 34.5% and 38.3% increases in LEP gene expression for a standard deviation (SD) increase in BMI and FMI, respectively. Increasing BMI (β = 0.0028, 95% CI: 0.0011, 0.0045), waist circumference (β = 0.0013, 95% CI: 0.0005, 0.0022), hip circumference (β = 0.0015, 95% CI: 0.0007, 0.0024), and FMI (β = 0.0041, 95% CI: 0.0015, 0.0067) were associated with higher LEPR protein expression. These associations equate to 16.8%, 17.6%, 17.7%, 17.2% increases in LEPR protein expression for a 1-SD increase in BMI, waist circumference, hip circumference, and FMI, respectively. Further, these associations were stronger among White and postmenopausal women and ER+ cases; formal tests of interaction yielded evidence of effect modification by race. No associations of body fatness with LEP protein expression, LEPR gene expression, or protein or gene expression of ADIPOQ, ADIPOR1, and ADIPOR2 were found., Conclusions: These findings support an association of increased body fatness - beyond overall body size measured using BMI - with higher LEP gene expression and higher LEPR protein expression in breast tumor tissues. Clarifying the impact of adiposity-related adipokine and adipokine receptor expression in breast tumors on long-term breast cancer outcomes is a critical next step., Competing Interests: Author EC is employed by the company Kaiser Permanente Northern California. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Llanos, Aremu, Cheng, Chen, Chekmareva, Cespedes Feliciano, Qin, Lin, Omene, Khoury, Hong, Yao, Ambrosone, Bandera and Demissie.)

Objective: To examine diabetes incidence in a diverse cohort of U.S. Hispanic/Latinos., Research Design and Methods: The Hispanic Community Health Study/Study of Latinos is a prospective cohort study with participants aged 18-74 years from four U.S. metropolitan areas. Participants were assessed for diabetes at the baseline examination (2008-2011), annually via telephone interview, and at a second examination (2014-2017)., Results: A total of 11,619 participants returned for the second examination. The overall age-adjusted diabetes incidence rate was 22.1 cases/1,000 person-years. The incidence was high among those with Puerto Rican and Mexican backgrounds as well as those aged ≥45 years and with a BMI ≥30 kg/m2. Significant differences in diabetes awareness, treatment, and health insurance coverage, but not glycemic control, were observed across Hispanic/Latino background groups, age groups, and BMI categories., Conclusions: Differences in diabetes incidence by Hispanic/Latino background, age, and BMI suggest the susceptibility of these factors., (© 2022 by the American Diabetes Association.)

Importance: Electronic frailty metrics have been developed for automated frailty assessment and include the Hospital Frailty Risk Score (HFRS), the Electronic Frailty Index (eFI), the 5-Factor Modified Frailty Index (mFI-5), and the Risk Analysis Index (RAI). Despite substantial differences in their construction, these 4 electronic frailty metrics have not been rigorously compared within a surgical population., Objective: To characterize the associations between 4 electronic frailty metrics and to measure their predictive value for adverse surgical outcomes., Design, Setting, and Participants: This retrospective cohort study used electronic health record data from patients who underwent abdominal surgery from January 1, 2010, to December 31, 2020, at 20 medical centers within Kaiser Permanente Northern California (KPNC). Participants included adults older than 50 years who underwent abdominal surgical procedures at KPNC from 2010 to 2020 that were sampled for reporting to the National Surgical Quality Improvement Program., Main Outcomes and Measures: Pearson correlation coefficients between electronic frailty metrics and area under the receiver operating characteristic curve (AUROC) of univariate models and multivariate preoperative risk models for 30-day mortality, readmission, and morbidity, which was defined as a composite of mortality and major postoperative complications., Results: Within the cohort of 37 186 patients, mean (SD) age, 67.9 (female, 19 127 [51.4%]), correlations between pairs of metrics ranged from 0.19 (95% CI, 0.18- 0.20) for mFI-5 and RAI 0.69 (95% CI, 0.68-0.70). Only 1085 of 37 186 (2.9%) were classified as frail based on all 4 metrics. In univariate models for morbidity, HFRS demonstrated higher predictive discrimination (AUROC, 0.71; 95% CI, 0.70-0.72) than eFI (AUROC, 0.64; 95% CI, 0.63-0.65), mFI-5 (AUROC, 0.58; 95% CI, 0.57-0.59), and RAI (AUROC, 0.57; 95% CI, 0.57-0.58). The predictive discrimination of multivariate models with age, sex, comorbidity burden, and procedure characteristics for all 3 adverse surgical outcomes improved by including HFRS into the models., Conclusions and Relevance: In this cohort study, the 4 electronic frailty metrics demonstrated heterogeneous correlation and classified distinct groups of surgical patients as frail. However, HFRS demonstrated the highest predictive value for adverse surgical outcomes.

Importance: Disadvantaged neighborhood-level and individual-level socioeconomic status (SES) have each been associated with suboptimal cancer care and inferior outcomes. However, independent or synergistic associations between neighborhood and individual socioeconomic disadvantage have not been fully examined, and prior studies using simplistic neighborhood SES measures may not comprehensively assess multiple aspects of neighborhood SES., Objective: To investigate the associations of neighborhood SES (using a validated comprehensive composite measure) and individual SES with survival among patients with nonmetastatic common cancers., Design, Setting, and Participants: This prospective, population-based cohort study was derived from the Surveillance, Epidemiology, and End Results-Medicare database from January 1, 2008, through December 31, 2011, with follow-up ending on December 31, 2017. Participants included older patients (≥65 years) with breast, prostate, lung, or colorectal cancer., Exposures: Neighborhood SES was measured using the area deprivation index (ADI; quintiles), a validated comprehensive composite measure of neighborhood SES. Individual SES was assessed by Medicare-Medicaid dual eligibility (yes vs no), a reliable indicator for patient-level low income., Main Outcomes and Measures: The primary outcome was overall mortality, and the secondary outcome was cancer-specific mortality. Hazard ratios (HRs) for the associations of ADI and dual eligibility with overall and cancer-specific mortality were estimated via Cox proportional hazards regression. Statistical analyses were conducted from January 23 to April 15, 2021., Results: A total of 96 978 patients were analyzed, including 25 968 with breast, 35 150 with prostate, 16 684 with lung, and 19 176 with colorectal cancer. Median age at diagnosis was 76 years (IQR, 71-81 years) for breast cancer, 73 years (IQR, 70-77 years) for prostate cancer, 76 years (IQR, 71-81 years) for lung cancer, and 78 years (IQR, 72-84 years) for colorectal cancer. Among lung and colorectal cancer patients, 8412 (50.4%) and 10 486 (54.7%), respectively, were female. The proportion of non-Hispanic White individuals among breast cancer patients was 83.7% (n = 21 725); prostate cancer, 76.8% (n = 27 001); lung cancer, 83.5% (n = 13 926); and colorectal cancer, 81.1% (n = 15 557). Neighborhood-level and individual-level SES were independently associated with overall mortality, and no interactions were detected. Compared with the most affluent neighborhoods (ADI quintile 1), living in the most disadvantaged neighborhoods (ADI quintile 5) was associated with higher risk of overall mortality (breast: HR, 1.34; 95% CI, 1.26-1.43; prostate: HR, 1.51; 95% CI, 1.42-1.62; lung: HR, 1.21; 95% CI, 1.14-1.28; and colorectal: HR, 1.24; 95% CI, 1.17-1.32). Individual socioeconomic disadvantage (dual eligibility) was associated with higher risk of overall mortality (breast: HR, 1.22; 95% CI, 1.15-1.29; prostate: HR, 1.29; 95% CI, 1.21-1.38; lung: HR, 1.14; 95% CI, 1.09-1.20; and colorectal: HR, 1.23; 95% CI, 1.17-1.29). A similar pattern was observed for cancer-specific mortality., Conclusions and Relevance: In this cohort study, neighborhood-level deprivation was associated with worse survival among patients with nonmetastatic breast, prostate, lung, and colorectal cancer, even after accounting for individual SES. These findings suggest that, in order to improve cancer outcomes and reduce health disparities, policies for ongoing investments in low-resource neighborhoods and low-income households are needed.

Plant-based diets are recommended for cancer survivors, but their relationship with breast cancer outcomes has not been examined. We evaluated whether long-term concordance with plant-based diets reduced the risk of recurrence and mortality among a prospective cohort of 3646 women diagnosed with breast cancer from 2005 to 2013. Participants completed food frequency questionnaires at diagnosis and 6-, 25-, and 72-month follow-up, from which we derived plant-based diet indices, including overall (PDI), healthful (hPDI), and unhealthful (uPDI). We observed 461 recurrences and 653 deaths over a median follow-up of 9.51 years. Using multivariable-adjusted Cox proportional hazards models, we estimated hazard ratios (HR) and 95% confidence intervals for breast cancer recurrence and all-cause, breast-cancer-specific, and non-breast-cancer mortality. Increased concordance with hPDI was associated with a reduced hazard of all-cause (HR 0.93, 95% CI: 0.83-1.05) and non-breast-cancer mortality (HR 0.83, 95% CI: 0.71-0.98), whereas increased concordance with uPDI was associated with increased hazards (HR 1.07, 95% CI: 0.96-1.2 and HR 1.20, 95% CI: 1.02-1.41, respectively). No associations with recurrence or breast-cancer-specific mortality were observed. In conclusion, healthful vs. unhealthful plant-based dietary patterns had differing associations with mortality. To enhance overall survival, dietary recommendations for breast cancer patients should emphasize healthful plant foods.

Background: There is an emerging viewpoint that change in body weight is not sufficiently sensitive to promptly identify clinically meaningful change in body composition, such as skeletal muscle depletion., Objectives: We aimed to determine whether body weight stability is associated with skeletal muscle depletion and whether skeletal muscle depletion is prognostic of death independently of change in body weight., Methods: This retrospective cohort included 1921 patients with stage I-III colorectal cancer. Computed tomography (CT)-based skeletal muscle characteristics and body weight were measured at diagnosis and after a mean 15.0-mo follow-up. Body weight stability was defined as weight change less than ±5% during follow-up. Sarcopenia and myosteatosis were defined using established thresholds for patients with cancer. Multivariable-adjusted logistic and flexible parametric proportional hazards survival models were used to quantify statistical associations., Results: At follow-up, 1026 (53.3%) patients were weight stable. Among patients with weight stability, incident sarcopenia and myosteatosis occurred in 8.5% (95% CI: 6.3%, 10.6%) and 13.5% (95% CI: 11.1%, 15.9%), respectively. Men were more likely to be weight stable than were women (56.7% compared with 49.9%; P = 0.04). Weight-stable men were less likely to develop incident sarcopenia (5.4% compared with 15.4%; P = 0.003) and myosteatosis (9.3% compared with 20.8%; P = 0.001) than weight-stable women. Among all patients, the development of incident sarcopenia (HR: 1.40; 95% CI: 1.02, 1.91) and of myosteatosis (HR: 1.41; 95% CI: 1.05, 1.90) were associated with a higher risk of death, independently of change in body weight. Patient sex did not modify the relation between skeletal muscle depletion and death., Conclusions: Body weight stability masks clinically meaningful skeletal muscle depletion. Body composition quantified using clinically acquired CT images may provide a vital sign to identify patients at increased risk of death. These data may inform the design of future cachexia trials., (© The Author(s) 2021. Published by Oxford University Press on behalf of the American Society for Nutrition.)

Poor diet quality is a leading risk factor for death in the United States. We examined the association between Healthy Eating Index-2015 (HEI-2015) scores and death from all causes, cardiovascular disease (CVD), cancer, Alzheimer disease, and dementia not otherwise specified (NOS) among postmenopausal women in the Women's Health Initiative Observational Study (1993-2017). This analysis included 59,388 participants who completed a food frequency questionnaire and were free of cancer, CVD, and diabetes at enrollment. Stratified Cox proportional hazards models were fit using person-years from enrollment as the underlying time metric. We estimated multivariable adjusted hazard ratios and 95% confidence intervals for risk of death associated with HEI-2015 quintiles, with higher scores reflecting more optimal diet quality. Over a median of 18.2 years, 9,679 total deaths 3,303 cancer deaths, 2,362 CVD deaths, and 488 deaths from Alzheimer disease and dementia NOS occurred. Compared with those with lower scores, women with higher HEI-2015 scores had an 18% lower risk of all-cause death and 21% lower risk of cancer death. HEI-2015 scores were not associated with death due to CVD, Alzheimer disease, and dementia NOS. Consuming a diet aligned with 2015-2020 US dietary guidelines may have beneficial impacts for preventing overall causes of death and death from cancer., (Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health 2020. This work is written by (a) US Government employee(s) and is in the public domain in the US.)

In the Women's Health Initiative (WHI), we investigated associations between baseline dual-energy X-ray absorptiometry (DXA) appendicular lean mass (ALM) and risk of incident fractures, falls, and mortality (separately for each outcome) among older postmenopausal women, accounting for bone mineral density (BMD), prior falls, and Fracture Risk Assessment Tool (FRAX ® ) probability. The WHI is a prospective study of postmenopausal women undertaken at 40 US sites. We used an extension of Poisson regression to investigate the relationship between baseline ALM (corrected for height 2 ) and incident fracture outcomes, presented here for major osteoporotic fracture (MOF: hip, clinical vertebral, forearm, or proximal humerus), falls, and death. Associations were adjusted for age, time since baseline and randomization group, or additionally for femoral neck (FN) BMD, prior falls, or FRAX probability (MOF without BMD) and are reported as gradient of risk (GR: hazard ratio for first incident fracture per SD increment) in ALM/height 2 (GR). Data were available for 11,187 women (mean [SD] age 63.3 [7.4] years). In the base models (adjusted for age, follow-up time, and randomization group), greater ALM/height 2 was associated with lower risk of incident MOF (GR = 0.88; 95% confidence interval [CI] 0.83-0.94). The association was independent of prior falls but was attenuated by FRAX probability. Adjustment for FN BMD T-score led to attenuation and inversion of the risk relationship (GR = 1.06; 95% CI 0.98-1.14). There were no associations between ALM/height 2 and incident falls. However, there was a 7% to 15% increase in risk of death during follow-up for each SD greater ALM/height 2 , depending on specific adjustment. In WHI, and consistent with our findings in older men (Osteoporotic Fractures in Men [MrOS] study cohorts), the predictive value of DXA-ALM for future clinical fracture is attenuated (and potentially inverted) after adjustment for femoral neck BMD T-score. However, intriguing positive, but modest, associations between ALM/height 2 and mortality remain robust. © 2021 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR)., (© 2021 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).)

Background: Prior research suggests a relationship between overall diet quality and breast cancer survival, although few studies have reported on this topic. We evaluated whether 4 dietary quality indices consistent with healthy eating recommendations around the time of breast cancer diagnosis were associated with risk of recurrence, cause-specific, and all-cause mortality., Methods: A total of 3660 women diagnosed with invasive breast cancer were included. Diet was assessed an average of 2.3 (range = 0.7-18.7) months after diagnosis, from which 4 dietary quality indices were derived: the American Cancer Society guidelines (ACS), the alternate Mediterranean Diet Index (aMED), the Dietary Approaches to Stop Hypertension (DASH), and the 2015 Healthy Eating Index (HEI). Over 40 888 person-years of follow-up, 461 breast cancer recurrences, and 655 deaths were ascertained. Cox models were used to estimate hazards ratios (HRs) and 95% confidence intervals (CIs)., Results: Adjusted comparisons between extreme quintiles showed all 4 dietary quality indices to be inversely associated with all-cause mortality, suggesting a 21%-27% lower risk (ACS HR = 0.73, 95% CI = 0.56 to 0.95; aMED HR = 0.79, 95% CI = 0.61 to 1.03; DASH HR = 0.76, 95% CI = 0.58 to 1.00; HEI HR = 0.77, 95% CI = 0.60 to 1.01). Similar patterns were noted for non-breast cancer mortality (ACS HR = 0.69, 95% CI = 0.48 to 0.98; aMED HR = 0.73, 95% CI = 0.50 to 1.05; DASH HR = 0.55, 95% CI = 0.38 to 0.79; HEI HR = 0.67, 95% CI = 0.48 to 0.94). None of the dietary quality indices were associated with recurrence or breast cancer-specific mortality., Conclusion: Food intake patterns concordant with dietary quality indices consistent with recommendations for healthy eating may be beneficial for women with breast cancer., (© The Author(s) 2021. Published by Oxford University Press.)

Low muscle is associated with an increased risk of chemotherapy-related dose limiting toxicities (DLT) in cancer patients. Resistance training (RT) improves muscle mass; however, the effects of RT on preventing DLTs and dose reductions in colon cancer patients has not been investigated. FOcus on Reducing dose-limiting toxicities in Colon cancer with resistance Exercise (FORCE) is a multicenter, randomized clinical trial examining the effects of RT on relative dose intensity (RDI; primary outcome) and moderate and severe chemotoxicities (primary outcome) in non-metastatic colon cancer patients receiving adjuvant chemotherapy. Patients (N = 180) will be recruited from Kaiser Permanente Northern California, Dana-Farber Cancer Institute, and Penn State Cancer Institute. This paper describes recruitment strategies and design considerations. Patients will be randomized in equal numbers to RT intervention or control. Patients have baseline and post completion of chemotherapy visits where information on anthropometry, physical function, body composition, quality of life, physical activity and dietary behaviors, and inflammatory blood markers will be collected. Patient-reported outcomes of chemotherapy side effects will be collected around the time of chemotherapy throughout the duration of the trial. Intervention participants will be prescribed a progressive RT program consisting of 4-6 visits with a certified exercise trainer, delivered either in-person or remotely by video conference, and will be asked to engage twice weekly in-home training sessions. Control patients at the end of the study receive a consult with a FORCE exercise trainer, an online exercise RT training program and a set of resistance bands. Results of this trial will provide information on the benefit of resistance exercise as a treatment to increase RDI., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Several studies have assessed the relationship between sleep duration and ovarian cancer risk, but the results are conflicting. Importantly, no studies addressed the relationship between sleep disturbance or sleep quality and ovarian cancer incidence. Moreover, few studies have examined the relationships between sleep measures and subtypes of ovarian cancer. This study included 109,024 postmenopausal women ages 50-79 from the Women's Health Initiative during 1993-1998 and followed through 2018. The Cox proportional hazards model was used to estimate adjusted HRs for the associations between sleep habits and the incidence of ovarian cancer and its subtypes. No association was observed between sleep duration, sleep quality, sleep disturbance, or insomnia and risk of overall ovarian cancer, serous/nonserous, or type I/type II ovarian cancer subtype. However, compared with women with average sleep quality, women with restful or very restful sleep quality had a significantly lower risk of invasive serous subtype [HR: 0.73, 95% confidence interval (CI): 0.60-0.90] while insomnia was associated with a higher risk of invasive serous subtype (HR: 1.36, 95% CI: 1.12-1.66). Associations with insomnia differed significantly by serous and nonserous subtypes, and type I and type II subtypes ( P heterogeneity = 0.001 and P heterogeneity <0.001, respectively). This study provides no evidence on association between sleep habits and overall ovarian cancer risk among postmenopausal women. However, restful or very restful sleep quality was associated with a lower risk of invasive serous ovarian cancer, and insomnia was associated with a higher risk of invasive serous ovarian cancer. Associations with insomnia differed by subtypes. PREVENTION RELEVANCE: This study shows no association between sleep duration, sleep quality, or insomnia with the risk of overall ovarian cancer among postmenopausal women. However, restful sleep quality was associated with a lower risk of invasive serous ovarian cancer, and insomnia was associated with a higher risk of invasive serous ovarian cancer., (©2020 American Association for Cancer Research.)

Background: Body composition from computed tomography (CT) scans is associated with cancer outcomes including surgical complications, chemotoxicity, and survival. Most studies manually segment CT scans, but Automatic Body composition Analyser using Computed tomography image Segmentation (ABACS) software automatically segments muscle and adipose tissues to speed analysis. Here, we externally evaluate ABACS in an independent dataset., Methods: Among patients with non-metastatic colorectal (n = 3102) and breast (n = 2888) cancer diagnosed from 2005 to 2013 at Kaiser Permanente, expert raters annotated tissue areas at the third lumbar vertebra (L3). To compare ABACS segmentation results to manual analysis, we quantified the proportion of pixel-level image overlap using Jaccard scores and agreement between methods using intra-class correlation coefficients for continuous tissue areas. We examined performance overall and among subgroups defined by patient and imaging characteristics. To compare the strength of the mortality associations obtained from ABACS's segmentations to manual analysis, we computed Cox proportional hazards ratios (HRs) and 95% confidence intervals (95% CI) by tertile of tissue area., Results: Mean ± SD age was 63 ± 11 years for colorectal cancer patients and 56 ± 12 for breast cancer patients. There was strong agreement between manual and automatic segmentations overall and within subgroups of age, sex, body mass index, and cancer stage: average Jaccard scores and intra-class correlation coefficients exceeded 90% for all tissues. ABACS underestimated muscle and visceral and subcutaneous adipose tissue areas by 1-2% versus manual analysis: mean differences were small at -2.35, -1.97 and -2.38 cm 2 , respectively. ABACS's performance was lowest for the <2% of patients who were underweight or had anatomic abnormalities. ABACS and manual analysis produced similar associations with mortality; comparing the lowest to highest tertile of skeletal muscle from ABACS versus manual analysis, the HRs were 1.23 (95% CI: 1.00-1.52) versus 1.38 (95% CI: 1.11-1.70) for colorectal cancer patients and 1.30 (95% CI: 1.01-1.66) versus 1.29 (95% CI: 1.00-1.65) for breast cancer patients., Conclusions: In the first study to externally evaluate a commercially available software to assess body composition, automated segmentation of muscle and adipose tissues using ABACS was similar to manual analysis and associated with mortality after non-metastatic cancer. Automated methods will accelerate body composition research and, eventually, facilitate integration of body composition measures into clinical care., (© 2020 The Authors. Journal of Cachexia, Sarcopenia and Muscle published by John Wiley & Sons Ltd on behalf of Society on Sarcopenia, Cachexia and Wasting Disorders.)

Importance: Given the risks of postoperative morbidity and its consequent economic burden and impairment to patients undergoing colon resection, evaluating risk factors associated with complications will allow risk stratification and the targeting of supportive interventions. Evaluation of muscle characteristics is an emerging area for improving preoperative risk stratification., Objective: To examine the associations of muscle characteristics with postoperative complications, length of hospital stay (LOS), readmission, and mortality in patients with colon cancer., Design, Setting, and Participants: This population-based retrospective cohort study was conducted among 1630 patients who received a diagnosis of stage I to III colon cancer from January 2006 to December 2011 at Kaiser Permanente Northern California, an integrated health care system. Preliminary data analysis started in 2017. Because major complication data were collected between 2018 and 2019, the final analysis using the current cohort was conducted between 2019 and 2020., Exposures: Low skeletal muscle index (SMI) and/or low skeletal muscle radiodensity (SMD) levels were assessed using preoperative computerized tomography images., Main Outcomes and Measures: Length of stay, any complication (≥1 predefined complications) or major complications (Clavien-Dindo classification score ≥3), 30-day mortality and readmission up to 30 days postdischarge, and overall mortality., Results: The mean (SD) age at diagnosis was 64.0 (11.3) years and 906 (55.6%) were women. Patients with low SMI or low SMD were more likely to remain hospitalized 7 days or longer after surgery (odds ratio [OR], 1.33; 95% CI, 1.05-1.68; OR, 1.39; 95% CI, 1.05-1.84, respectively) and had higher risks of overall mortality (hazard ratio, 1.40; 95% CI, 1.13-1.74; hazard ratio, 1.44; 95% CI, 1.12-1.85, respectively). Additionally, patients with low SMI were more likely to have 1 or more postsurgical complications (OR, 1.31; 95% CI, 1.04-1.65) and had higher risk of 30-day mortality (OR, 4.85; 95% CI, 1.23-19.15). Low SMD was associated with higher odds of having major complications (OR, 2.41; 95% CI, 1.44-4.04)., Conclusions and Relevance: Low SMI and low SMD were associated with longer LOS, higher risk of postsurgical complications, and short-term and long-term mortality. Research should evaluate whether targeting potentially modifiable factors preoperatively, such as preserving muscle mass, could reverse the observed negative associations with postoperative outcomes.

Importance: Understanding changes in frailty in relation to cancer diagnosis can inform optimal selection of cancer treatments and survivorship care., Objective: To investigate associations of prediagnostic frailty and change in frailty status with mortality after a cancer diagnosis., Design, Setting, and Participants: This multicenter, prospective cohort study included 7257 community-dwelling, postmenopausal women in the United States who had frailty assessed at the Women's Health Initiative (WHI) enrollment (1993-1998) and the 3-year visit who were subsequently diagnosed as having invasive cancer. The data were analyzed from January 7, 2019, to June, 8, 2020., Exposure: Frailty scores were defined from validated questionnaire items conceptually aligned with the Fried frailty phenotype, including at least 3 of the following characteristics: self-reported unintentional weight loss, exhaustion, low physical activity, and muscle weakness or impaired walking. Physical function components of the frailty score were updated a median of 10 (range, 1-18) times., Main Outcomes and Measures: Using multivariable-adjusted Cox proportional hazards models, this study examined associations of prediagnostic frailty (at the 3-year visit, before cancer diagnosis) and prediagnostic changes in frailty (from enrollment to the 3-year visit) with mortality. Women were followed up beginning from cancer diagnosis for mortality outcomes through March 2018. In linear mixed-effects models with frailty scores as a function of time since cancer diagnosis, this study evaluated whether the time slope, ie, the rate of change in frailty score, increased after cancer diagnosis., Results: This study included 7257 women in the WHI cohort who completed frailty assessments at enrollment and the 3-year WHI visit before cancer diagnosis and subsequently developed cancer. Cancer cases included 2644 breast cancers (36%), 822 lung cancers (11%), 691 colorectal cancers (10%), 445 endometrial cancers (6%), and 286 ovarian cancers (4%). At the 3-year visit, prior to cancer diagnosis, the mean (SD) age was 63 (7) years, and 1161 of 7257 (16%) of participating women met criteria for frailty; 2129 of 7257 (29%) were prefrail, and 3967 of 7257 (55%) were nonfrail. Over a median follow-up of 5.8 years after cancer diagnosis (range, 1 day to 19.9 years), 3056 women died. After multivariable adjustment, women who were frail (vs nonfrail) before cancer diagnosis had an increased risk of mortality after cancer diagnosis (hazard ratio [HR], 1.40; 95% CI, 1.26-1.55; P for trend <.001). Sustained frailty (21% [1537 of 7257] of women) or worsening frailty (22% [1578 of 7257]) vs being consistently nonfrail (45% [3266 of 7257]) before cancer diagnosis increased the risk of mortality after cancer diagnosis (HR, 1.25; 95% CI, 1.14-1.38 and 1.22; 95% CI, 1.11-1.34, respectively; P for trend <.001). In linear mixed-effects models, the rate of increase in physical frailty over time was statistically significantly higher after cancer diagnosis., Conclusions and Relevance: Sustained and worsening frailty before cancer diagnosis was associated with an increased risk of mortality after cancer diagnosis in postmenopausal women. Furthermore, the rate of decline in physical function accelerated after cancer diagnosis. Frailty assessment could provide valuable information and perhaps prompt interventions to reduce and preempt worsening of physical frailty after cancer diagnosis.

Background: Physical activity is frequently proposed as an intervention to reduce fatigue and sleep disturbance in cancer survivors; however, the long-term effects of physical activity are often not reported, and older adults are typically excluded from these intervention studies., Objectives: This article aimed to examine if postdiagnosis physical activity is associated with lower long-term fatigue and sleep disturbance in older adult breast cancer survivors., Methods: Data were analyzed of a prospective cohort of 440 breast cancer survivors aged 65 years or older from the Women's Health Initiative study. Multiple linear and logistic regression models were used to examine associations of physical activity with fatigue and sleep disturbance., Findings: Higher postdiagnosis physical activity was associated with lower long-term fatigue but was not associated with lower sleep disturbance after adjusting for demographics, cancer characteristics, and baseline measures.

Background: We previously showed that a food-based empirical dietary inflammatory pattern (EDIP) score is associated with circulating inflammatory biomarkers. Metabolomic profiling of inflammatory diets may therefore provide insights on mechanisms contributing to disease etiology and prognosis. We aimed to elucidate metabolites associated with inflammatory diets among postmenopausal women, utilizing a robust study design that incorporates independent discovery and validation datasets., Methods: This baseline cross-sectional investigation evaluated associations between continuous EDIP scores calculated from food frequency questionnaires and 448 log-transformed plasma metabolites as outcomes in multivariable-adjusted linear regression analyses. Metabolites were measured with liquid chromatography tandem mass spectroscopy. Metabolite discovery was conducted among 1109 Women's Health Initiative (WHI) Hormone Therapy trial participants and results were replicated in an independent dataset of 810 WHI Observational Study participants. Secondary analyses were stratified by standard body mass index (BMI, kg/m 2 ) categories. In discovery and replication datasets statistical significance was based on false-discovery rate adjusted P < 0.05., Results: After adjusting for energy intake, BMI, physical activity, and other confounding variables, 23 metabolites were significantly associated with EDIP score in the discovery dataset. Of these, the following ten were replicated: trigonelline, caffeine, acethylamino-6-amino-3-methyluracil, 7-methylxanthine, 1,7-dimethyluric acid, 3-methylxanthine, C18:3CE, glycine, associated with lower dietary inflammatory potential; whereas C52:3 triacylglycerol and linoleate associated with higher dietary inflammatory potential. Four of the ten were associated [glycine (inversely), caffeine, 1,7-dimethyluric acid, C52:3 triacylglycerol, (positively)], with C-reactive protein levels. In secondary analyses, associations showed differences by BMI category. Four metabolites, related to coffee/caffeine metabolism were inversely associated among normal weight women, and 83 metabolites associated with EDIP among overweight/obese women, including 40 (48%) that were also associated with C-reactive protein., Conclusion: Metabolites associated with coffee/caffeine and lipid metabolism may reflect the inflammatory potential of diet. Potential differences by BMI and the linkage to disease outcomes, require further study., (Copyright © 2019 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.)

Background: The quantity and distribution of adipose tissue may be prognostic measures of mortality in colorectal cancer patients, and such associations may vary by patient sex., Methods: This cohort included 3262 stage I-III colorectal cancer patients. Visceral and subcutaneous adipose tissues were quantified using computed tomography. The primary endpoint was all-cause mortality. Restricted cubic splines estimated statistical associations with two-sided P values., Results: Visceral adipose tissue was prognostic of mortality in a reverse L-shaped pattern (nonlinear P = .02); risk was flat to a threshold (∼260 cm2) then increased linearly. Subcutaneous adipose tissue was prognostic of mortality in a J-shaped pattern (nonlinear P < .001); risk was higher at extreme (<50 cm2) but lower at intermediate values (>50 to ≤560 cm2). Patient sex modified the prognostic associations between visceral adipose tissue (Pinteraction = .049) and subcutaneous adipose tissue (Pinteraction = .04) with mortality. Among men, visceral adiposity was associated with mortality in a J-shaped pattern (nonlinear P = .003), whereas among women, visceral adiposity was associated with mortality in a linear pattern (linear P = .008). Among men, subcutaneous adiposity was associated with mortality in an L-shaped pattern (nonlinear P = .01), whereas among women, subcutaneous adiposity was associated with mortality in a J-shaped pattern (nonlinear P < .001)., Conclusions: Visceral and subcutaneous adipose tissue were prognostic of mortality in patients with colorectal cancer; the shape of these associations were often nonlinear and varied by patient sex. These results offer insight into the potential biological mechanisms that link obesity with clinical outcomes in patients with cancer, suggesting that the dysregulated deposition of excess adiposity is prognostic of mortality., (© The Author(s) 2019. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Importance: Although most chemotherapies are dosed on body surface area or weight, body composition (ie, the amount and distribution of muscle and adipose tissues) is thought to be associated with chemotherapy tolerance and adherence., Objectives: To evaluate whether body composition is associated with relative dose intensity (RDI) on anthracycline and taxane-based chemotherapy or hematologic toxic effects and whether lower RDI mediates the association of adiposity with mortality., Design, Setting, and Participants: An observational cohort study with prospectively collected electronic medical record data was conducted at Kaiser Permanente Northern California, a multicenter, community oncology setting within an integrated health care delivery system. Participants included 1395 patients with nonmetastatic breast cancer diagnosed between January 1, 2005, and December 31, 2013, and treated with anthracycline and taxane-based chemotherapy. Data analysis was performed between February 25 and September 4, 2019., Exposures: Intramuscular, visceral, and subcutaneous adiposity as well as skeletal muscle were evaluated from clinically acquired computed tomographic scans at diagnosis., Main Outcomes and Measures: The primary outcome was low RDI (<0.85), which is the ratio of delivered to planned chemotherapy dose, derived from infusion records; in addition, hematologic toxic effects were defined based on laboratory test values. To evaluate associations with overall and breast cancer-specific mortality, logistic regression models adjusted for age and body surface area were fit as well as Cox proportional hazards models adjusted for age, race/ethnicity, adiposity, Charlson comorbidity index score, and tumor stage and subtype. The mediation proportion was computed using the difference method., Results: The mean (SD) age at diagnosis of the 1395 women included in the study was 52.8 (10.2) years. Greater visceral (odds ratio [OR], 1.19; 95% CI, 1.02-1.39 per SD) and intramuscular (OR, 1.16; 95% CI, 1.01-1.34 per SD) adiposity were associated with increased odds of RDI less than 0.85. Greater muscle mass was associated with a decreased odds of hematologic toxic effects (OR, 0.84; 95% CI, 0.71-0.98 per SD). Relative dose intensity less than 0.85 was associated with a 30% increased risk of death (hazard ratio, 1.30; 95% CI, 1.02-1.65). Lower RDI partially explained the association of adiposity with breast cancer-specific mortality (mediation proportion, 0.20; 95% CI, 0.05-0.55)., Conclusions and Relevance: Excess adiposity, presenting as larger visceral or intramuscular adiposity, was associated with lower RDI. Lower RDI partially mediated the association of adiposity with worse breast cancer-specific survival. Body composition may help to identify patients likely to experience toxic effects and subsequent dose delays or reductions, which could compromise chemotherapeutic efficacy.

Importance: Inadequate sleep duration and quality increase the risk of obesity. Sleep timing, while less studied, is important in adolescents because increasing evening preferences (chronotypes), early school start times, and irregular sleep schedules may cause circadian misalignment., Objective: To investigate associations of chronotype and social jet lag with adiposity and cardiometabolic risk in young adolescents., Design, Setting, and Participants: Starting in 1999, Project Viva recruited pregnant women from eastern Massachusetts. Mother-child in-person visits occurred throughout childhood. From January 23, 2012, to October 16, 2016, 804 adolescents aged 12 to 17 years completed 5 days or more of wrist actigraphy, questionnaires, and anthropometric measurements. A cross-sectional analysis using these data was conducted from April 31, 2018, to May 1, 2019., Exposures: Chronotype, measured via a continuous scale with higher scores indicating greater evening preferences, and social jet lag, measured as the continuous difference in actigraphy sleep midpoint in hours from midnight on weekends vs weekdays, with higher values representing more delayed sleep timing on weekends., Main Outcomes and Measures: Adiposity, measured via anthropometry and dual-energy x-ray absorptiometry. For a subset of 479 adolescents with blood samples, cardiometabolic risk scores were computed as the mean of 5 sex- and cohort-specific z scores for waist circumference, systolic blood pressure, inversely scaled high-density lipoprotein cholesterol, and log-transformed triglycerides and homeostatic model of insulin resistance., Results: Among the 804 adolescents in the study, 418 were girls and 386 were boys, with a mean (SD) age of 13.2 (0.9) years. In multivariable models adjusted for age, puberty, season, and sociodemographics, associations of chronotype and social jet lag with adiposity varied by sex. For girls, greater evening preference was associated with a 0.58-cm (95% CI, 0.12-1.03 cm; P = .04 for interaction) higher waist circumference and 0.16 kg/m2 (95% CI, 0.01-0.31 kg/m2; P = .03 for interaction) higher fat mass index as measured by dual-energy x-ray absorptiometry; each hour of social jet lag was associated with a 1.19-cm (95% CI, 0.04-2.35 cm; P = .21 for interaction) higher waist circumference and 0.45 kg/m2 (95% CI, 0.09-0.82 kg/m2; P = .01 for interaction) higher fat mass index as measured by dual-energy x-ray absorptiometry. Associations of social jet lag and evening chronotypes persisted for many measures of adiposity after adjustment for sleep duration and other lifestyle behaviors. By contrast, no associations were observed in boys. There were no associations with the cardiometabolic risk score for either sex, although statistical power was low for this outcome., Conclusions and Relevance: Evening chronotypes and social jet lag were associated with greater adiposity in adolescent girls but not adolescent boys. Interventions aimed at improving sleep schedules may be useful for obesity prevention, especially in girls.

Purpose: Cardiovascular disease (CVD) is a major source of morbidity and mortality among breast cancer survivors. Although body mass index (BMI) is associated with CVD risk, adipose tissue distribution may better identify patients with a high risk of CVD after breast cancer., Methods: Among 2,943 patients with nonmetastatic breast cancer without prior CVD, we used International Classification of Diseases (9th and 10th revisions) codes to identify incidence of nonfatal stroke, myocardial infarction, heart failure, or CVD death. From clinically acquired computed tomography scans obtained near diagnosis, we measured visceral adiposity (centimeters squared), subcutaneous adiposity (centimeters squared), and intramuscular adiposity (fatty infiltration into muscle [Hounsfield Units, scored inversely]). We estimated hazard ratios (HRs) and 95% CIs per SD increase in adiposity accounting for competing risks and adjusting for demographics, smoking, cancer treatment, and pre-existing CVD risk factors., Results: Mean (SD) age was 56 (12) years. Over a median follow-up of 6 years, 328 CVD events occurred. Each SD increase in visceral or intramuscular adiposity was associated with an increase in CVD risk (HR, 1.15 [95% CI, 1.03 to 1.29] and HR, 1.21 [95% CI, 1.06 to 1.37]), respectively). Excess visceral and intramuscular adiposity occurred across all BMI categories. Among normal-weight patients, each SD greater visceral adiposity increased CVD risk by 70% (HR, 1.70 [95% CI, 1.10 to 2.62])., Conclusion: Visceral and intramuscular adiposity were associated with increased CVD incidence after breast cancer diagnosis, independent of pre-existing CVD risk factors and cancer treatments. The increased CVD incidence among normal-weight patients with greater visceral adiposity would go undetected with BMI alone. Measures of adipose tissue distribution may help identify high-risk patients and tailor CVD prevention strategies.

Purpose: Emerging data indicate that the timing and rhythms of energetic behaviors may influence metabolism and obesity risk. Our aim was to derive diurnal rest-activity patterns from actigraphy in adolescents and analyze associations with adiposity measures and cardiometabolic risk factors., Methods: Adolescents in the Project Viva cohort wore a wrist actigraph over 7 days. We derived markers of daily rest-activity patterns from actigraphy using nonparametric models, generating measurements of relative amplitude (RA). RA reflects the normalized difference in activity measured during the most active 10-hour period and the least active 5-hour period, averaged over multiple 24-hour periods. Using multivariable-adjusted linear regression models, we estimated associations of RA and its components with markers of adiposity (body mass index, waist circumference, skinfolds, dual-energy X-ray absorptiometry fat mass) and cardiometabolic health (cardiometabolic risk score, derived as the mean of five sex-specific internal z-scores for waist circumference, systolic blood pressure, high-density lipoprotein cholesterol scaled inversely, and log-transformed triglycerides and homeostatic model assessment of insulin resistance)., Results: A total of 778 adolescents provided at least 5 days of valid actigraphy data. The average age was 13.2 (±.9) years, 52% were female, and the average RA was .9 (±.1). A higher RA reflecting higher activity during wakefulness and lower activity during the night was associated with more favorable indices of adiposity (e.g., -.35 kg/m 2 lower body mass index per each .04 units increment of RA; 95% confidence interval: -.60 to -.09)., Conclusions: In this large sample of adolescents, a higher RA emerged as a novel biomarker, associated with more favorable cardiometabolic profiles., (Copyright © 2019 Society for Adolescent Health and Medicine. Published by Elsevier Inc. All rights reserved.)

In diseases such as cancer, patients suffer from degenerative loss of skeletal muscle (cachexia). Muscle wasting and loss of muscle function/performance (sarcopenia) can also occur during advanced aging. Assessing skeletal muscle mass in sarcopenia and cachexia is therefore of clinical interest for risk stratification. In comparison with fat, body fluids and bone, quantifying the skeletal muscle mass is more challenging. Computed tomography (CT) is one of the gold standard techniques for cancer diagnostics and analysis of progression, and therefore a valuable source of imaging for in vivo quantification of skeletal muscle mass. In this paper, we design a novel deep neural network-based algorithm for the automated segmentation of skeletal muscle in axial CT images at the third lumbar (L3) and the fourth thoracic (T4) levels. A two-branch network with two training steps is investigated. The network's performance is evaluated for three trained models on separate datasets. These datasets were generated by different CT devices and data acquisition settings. To ensure the model's robustness, each trained model was tested on all three available test sets. Errors and the effect of labeling protocol in these cases were analyzed and reported. The best performance of the proposed algorithm was achieved on 1327 L3 test samples with an overlap Jaccard score of 98% and sensitivity and specificity greater than 99%., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Importance: Patients with colorectal cancer (CRC) are up to 4-fold more likely than individuals without a history of cancer to develop cardiovascular disease. Clinical care guidelines recommend that physicians counsel patients with CRC regarding the association between obesity (defined using body mass index [BMI] calculated as weight in kilograms divided by height in meters squared) and cardiovascular disease risk; however, this recommendation is based on expert opinion., Objective: To determine which measures of body composition are associated with major adverse cardiovascular events (MACEs) in patients with CRC., Design, Setting, and Participants: Population-based retrospective cohort study of 2839 patients with stage I to III CRC diagnosed between January 2006 and December 2011 at an integrated health care system in North America., Exposures: The primary exposures were BMI and computed tomography-derived body composition measurements (eg, adipose tissue compartments and muscle characteristics) obtained at the diagnosis of CRC., Main Outcomes and Measures: The primary outcome was time to the first occurrence of MACE after diagnosis of CRC, including myocardial infarction, stroke, and cardiovascular death., Results: In this population-based cohort study of 2839 participants with CRC (1384 men and 1455 women), the average age (SD) was 61.9 (11.5) years (range, 19-80 years). A substantial number of patients were former (1127; 40%) or current smokers (340; 12%), with hypertension (1150; 55%), hyperlipidemia (1389; 49%), and type 2 diabetes (573; 20%). The cumulative incidence of MACE 10 years after diagnosis of CRC was 19.1%. Body mass index was positively correlated with some computed tomography-derived measures of body composition. However, BMI was not associated with MACE; contrasting BMI categories of greater than or equal to 35 vs 18.5 to 24.9, the hazard ratio (HR) was 1.23 (95% CI, 0.85-1.77; P = .50 for trend). Visceral adipose tissue area was associated with MACE; contrasting the highest vs lowest quintile, the HR was 1.54 (95% CI, 1.02-2.31; P = .04 for trend). Subcutaneous adipose tissue area was not associated with MACE; contrasting the highest vs lowest quintile, the HR was 1.15 (95% CI, 0.78-1.69; P = .65 for trend). Muscle mass was not associated with MACE; contrasting the highest vs lowest quintile, the HR was 0.96 (95% CI, 0.57-1.61; P = .92 for trend). Muscle radiodensity was associated with MACE; contrasting the highest (ie, less lipid stored in the muscle) vs lowest quintile, the HR was 0.67 (95% CI, 0.44-1.03; P = .02 for trend)., Conclusions and Relevance: Visceral adiposity and muscle radiodensity appear to be risk factors for MACE. Body mass index may have limited use for determining cardiovascular risk in this patient population.